Fluorination process

Abstract

Compounds of formula (II), (IIIa) or (IIIb) (variables are described in the specification) are prepared by fluorination of β,γ-unsaturated alkyl silanes. These compounds are useful as building blocks in the pharmaceutical industry.

1. A process for producing a compound of formula (IIIa) 
       
         
           
           
               
               
           
         
       
       wherein
 R 4  is selected from hydrogen, -alk-H, aryl, -alk-aryl, —O-aryl, —O-alk-aryl-, -alk-O-aryl, -alk-O-alk-aryl, —O-alk-H, -alk-O-alk-H, —C(O)-aryl, —C(O)-alk-aryl, -alk-C(O)-aryl, -alk-C(O)-alk-aryl, —C(O)-alk-H, -alk-C(O)-alk-H, —C(O)N(-alk-H)C(O)O-alk-H, -alk-C(O)N(-alk-H)C(O)O-alk-H, wherein when R 4  is an unsubstituted or substituted hydrocarbon group with two or more carbon atoms it is saturated between C1 and C2; 
 R 10  is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and phenyl; 
 R 11  and R 12 , together with the nitrogen atom to which they are attached, represent an N-oxazolidinyl group which is substituted by R 10  or -alk-R 10 ; 
 -alk- is a straight or branched C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group which is unsubstituted or substituted by halogen; 
 R 1 , R 2  and R 3  are independently selected from C 1-6 alkyl and phenyl, wherein at least one of R 1 , R 2  and R 3  is not methyl; 
 L is a C 1-3 alkylene group which is unsubstituted or substituted by one or more groups independently selected from R 10 , aryl, -alk-aryl, —C(O)O-alk-H and —C(O)—NR 11 R 12 ; and Nu is —C(O)O—; or L is a C 2-4 alkylene group which is unsubstituted or substituted by one or more groups independently selected from R 10 , aryl, -alk-aryl, —C(O)O-alk-H and —C(O)—NR 11 R 12 ; and Nu is —O—; 
 
       by attaching a fluoro group gamma to a silane group, which process comprises contacting a source of electrophilic fluorine with a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2  and R 3  are independently selected from C 1-6 alkyl and phenyl and at least one of R 1 , R 2  and R 3  is not methyl; G is —C(R 4 )(R 5 )—, R 4  is as defined above, R 5 , R 6  and R 8  are hydrogen; R 7  is -L-NuH; L and Nu are as defined above; and the compound produced is of formula (IIIa) as defined above. 
 
     
     
       2. A process according to  claim 1  wherein, the source of electrophilic fluorine is [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)]. 
     
     
       3. A process according to  claim 1  wherein L is a C 1 alkylene or C 2 alkylene group and Nu is —C(O)O—, or L is a C 2 alkylene or C 3 alkylene group and Nu is —O—. 
     
     
       4. A process according to  claim 1  wherein L is unsubstituted. 
     
     
       5. A process according to  claim 1  wherein R 4  is H or -alk-H and (i) L is an ethylene group which is unsubstituted or substituted by one or more of R 10 , aryl and -alk-aryl and Nu is —O—; or (ii) L is a methylene group which is unsubstituted or substituted by one or more of R 10 , aryl and -alk-aryl and Nu is —C(O)O—. 
     
     
       6. A process according to  claim 5  wherein R 4  is H. 
     
     
       7. A process according to  claim 5  wherein either (i) L is an ethylene group substituted by a phenylethyl group alpha to Nu and Nu is —O—, or (ii) L is an unsubstituted methylene or ethylene group and Nu is —C(O)O—. 
     
     
       8. A process according to  claim 7  wherein SiR 1 R 2 R 3  is an Si i Pr 3  group. 
     
     
       9. A process according to  claim 1  wherein said aryl groups contain from 6 to 10 carbon atoms and are unsubstituted or substituted with one or two substituents, which substituents are selected from the group consisting of nitro, halo, C 1-6 alkyl and C 1-6 alkoxy. 
     
     
       10. A process according to  claim 1  wherein R 1 , R 2  and R 3  are each selected from methyl, ethyl, t-butyl, i-propyl and phenyl. 
     
     
       11. A process according to  claim 1  wherein SiR 1 R 2 R 3  is SiMe 2   t Bu, Si i Pr 3 , SiPh i Pr 2 , Si t BuPh 2  or SiPh 3 . 
     
     
       12. A process according to  claim 1  wherein R 4  is selected from hydrogen and C 1-6 alkyl.